US10105555B2 - System and method for determining radiation dose to circulating blood - Google Patents

System and method for determining radiation dose to circulating blood Download PDF

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US10105555B2
US10105555B2 US15/115,153 US201515115153A US10105555B2 US 10105555 B2 US10105555 B2 US 10105555B2 US 201515115153 A US201515115153 A US 201515115153A US 10105555 B2 US10105555 B2 US 10105555B2
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radiation
dose
site
blood
tumor volume
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Susannah ELLSWORTH
Eric Ford
Stuart A. Grossman
Robert Hobbs
Lawrence KLEINBERG
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Johns Hopkins University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1048—Monitoring, verifying, controlling systems and methods
    • A61N5/1071—Monitoring, verifying, controlling systems and methods for verifying the dose delivered by the treatment plan

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  • the present invention relates generally to systems or methods of using such systems to calculate the radiation dose received by circulating blood cells during a course of external beam radiotherapy.
  • the present invention also discloses systems or methods of applying such systems to identify circulating blood as an organ at risk in radiation therapy.
  • CD4 counts were >450/ ⁇ L in all patients before starting therapy, but that during treatment, approximately one-fourth developed CD4 counts ⁇ 200/ ⁇ L [Hughes M A, Parisi M, Grossman S, Kleinberg L. Primary brain tumors treated with steroids and radiotherapy: Low CD4 counts and risk of infection. Int J Radiat Oncol Biol Phys 2005; 62(5):1423-1426. doi: 10.1016/j.ijrobp.2004.12.085]. After temozolomide became standard therapy, a second study prospectively evaluated serial lymphocyte counts in high-grade glioma patients receiving radiation and temozolomide.
  • lymphotoxic agents corticosteroids, temozolomide, and radiation therapy
  • radiation may play an important role in lymphopenia. Lymphopenia following radiation therapy was first described in the early 20th century, only a few years after x-rays were discovered, and has since been documented to occur after either external beam radiotherapy or brachytherapy directed to virtually every part of the body [Shohan J. Some theoretical considerations on the present status of roentgen therapy. N Engl J Med 1916; 175:321-327]. Radiation can induce lymphopenia regardless of whether chemotherapy or steroids are given concurrently or whether bone marrow or lymphatic tissue is included in the field.
  • irradiation of the brain which contains neither bone marrow nor lymphatic tissue, can cause over a 60% reduction in the lymphocyte count [MacLennan I C, Kay H E. Analysis of treatment in childhood leukemia. IV. The critical association between dose fractionation and immunosuppression induced by cranial irradiation. Cancer 1978; 41(1):108-111].
  • radiation of extracorporeal blood in patients undergoing renal dialysis can result in profound and durable lymphopenia [Weeke E. The development of lymphopenia in uremic patients undergoing extracorporeal irradiation of the blood with portable beta units. Radiat Res 1973; 56(3):554-559].
  • the present invention overcomes the aforementioned drawbacks by providing systems or methods of applying such systems to calculate the dose received by circulating blood during a course of external beam radiotherapy.
  • the present invention discloses a non-transitory, computer readable storage medium having instructions stored thereon that, when executed by a computer processor, cause the computer processor to receive medical imaging data from a subject including information about a treatment site receiving a dose of radiation, receive a plurality of subject/treatment-specific variables including at least two of a target volume size associated with the dose of radiation, a radiation treatment technique associated with the dose of radiation, a dose rate associated with the dose of radiation, a total dose associated with the dose of radiation, a fraction size associated with the dose of radiation, a treatment time associated with delivering the dose of radiation, a speed of circulating blood within the subject, and a presence of vasculature relative to the treatment site; and determine using the plurality of subject/treatment-specific variables a as quantity of radiation received by circulating blood within the subject when receiving the dose of radiation.
  • the present invention discloses a method of using the above system to calculate the dose received by circulating blood during a course of external beam radiotherapy.
  • the method comprise the steps of obtaining medical imaging data of a site in a patient; creating a tumor volume within the site using the medical imaging data; determining a dose of radiation delivered to the site including the tumor volume and surrounding normal tissues; generating a three-dimensional dose grid for the site; using the three-dimensional dose grid for the site, calculating a distribution of radiation dose to a blood pool that is either within or transits through the site; generating dose volume histograms for the blood or its constituents as normal organs; and generating a report indicating the dose of radiation received by circulating blood using the quantification.
  • the present invention discloses a computer system for calculating radiation doses received by circulating blood cells in a patient, the computer system comprising an input interface unit to load pre-obtained medical imaging data of a site in a patient into the system and a processor.
  • the processor is configured to carry on the steps of creating a tumor volume within the site using the medical imaging data, determining a dose of radiation delivered to the site using the tumor volume and surrounding normal tissues, and generating a three-dimensional dose grid for the site.
  • the processor is also configured to carry out the steps of calculating a dose of radiation to a blood pool within or transiting through the site defining a radiation dose distribution to the blood volume considered as a whole.
  • the system also includes a display to display the calculating radiation doses received by circulating blood cells in a patient.
  • FIG. 1 is a flow chart setting forth the steps undertaken by a computer processor under instructions of computer readable storage mediums according to embodiments of the present invention.
  • FIG. 2 is a flow chart setting forth the steps of methods for calculating radiation doses received by circulating blood cells during a course of external beam radiotherapy.
  • FIG. 6 is a block diagram showing a computer system for calculating radiation doses received by circulating blood cells according to one embodiment of the present invention.
  • the term “subject” or “individual” refers to a human or other vertebrate animal. It is intended that the term encompass “patients.”
  • CT computed tomography
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • CT produces a volume of data that can be manipulated in order to demonstrate various bodily structures based on their ability to block the x-ray beam.
  • images generated were in the axial or transverse plane, perpendicular to the long axis of the body, modern scanners allow this volume of data to be reformatted in various planes or even as volumetric (3D) representations of structures.
  • Radiation therapy refers to the medical use of ionizing radiation, generally as part of cancer treatment to control or kill malignant cells.
  • Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor (for example, early stages of breast cancer).
  • Radiation therapy may be synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers.
  • lymphocyte refers to a type of white blood cell in the vertebrate immune system. Specifically, lymphocyte may be used as a landmark of the adaptive immune system.
  • radiation treatment plan refers to the process in which a team consisting of radiation oncologists, radiation therapist, medical physicists and medical dosimetrists plan the appropriate external beam radiotherapy or internal brachytherapy treatment technique for a patient with cancer.
  • medical imaging for example, x-ray computed tomography often the primary image set for treatment planning, magnetic resonance imaging excellent secondary image set for soft tissue contouring, and positron emission tomography less commonly used and reserved for cases where specific uptake studies can enhance planning target volume delineation
  • treatment simulations are used to plan the geometric, radiological, and dosimetric aspects of the therapy using radiation transport simulations and optimization.
  • intensity modulated radiation therapy this process involves selecting the appropriate beam energy (photons, and perhaps protons), energy (for example, 6 MV, 18 MV) and arrangements.
  • brachytherapy involves selecting the appropriate catheter positions and source dwell times (in HDR brachytherapy) or seeds positions (in LDR brachytherapy). Plans are often assessed with the aid of dose-volume histograms, allowing the clinician to evaluate the uniformity of the dose to the diseased tissue (tumor) and sparing of healthy structures.
  • the present invention generally applies to a mammalian species. In one preferred embodiment, the present invention applies to humans.
  • the present invention discloses a non-transitory, computer readable storage medium having instructions stored thereon that, when executed by a computer processor, cause the computer processor to determine radiation doses received by circulating blood within the subject when receiving the dose of radiation.
  • FIG. 1 is a flow chart setting forth the steps according to some examples of the present invention. As shown in FIG. 1 , the process begins with receiving medical imaging data from a subject including information about a treatment site receiving a dose of radiation (S 101 ). Likewise, a plurality of subject/treatment-specific variables are provided to the system (S 102 ).
  • subject/treatment-specific variables may include a target volume size associated with the dose of radiation, a radiation treatment technique associated with the dose of radiation, a dose rate associated with the dose of radiation, a total dose associated with the dose of radiation, a fraction size associated with the dose of radiation, a treatment time associated with delivering the dose of radiation, a speed of circulating blood within the subject, and a presence of vasculature relative to the treatment site, As described herein, the present invention may be implemented with any combination of the above-described variables, such as only one or two or even all of these or other variables.
  • the medical imaging data and the plurality of subject/treatment-specific variables are then used as inputs to a model that, as will be described, allows the calculation of radiation received by circulating blood within the subject when receiving the dose of radiation.
  • the present invention discloses methods for calculating the radiation doses received by circulating blood cells such as lymphocytes.
  • the present methods may be applicable for determining the radiation doses received by circulating blood cells through any site in a patient.
  • a suitable site in a patient may include head, heart, lung, and other tissues or organs.
  • a suitable site may be head.
  • FIG. 2 is a flow chart setting forth the steps of methods for calculating the dose received by circulating blood during a course of external beam radiotherapy.
  • a method for calculating radiation doses received by circulating blood cells in a patient may include the steps of obtaining medical imaging data of a site in a patient (S 201 ).
  • Many medical imaging data may be suitable for the present invention.
  • one suitable medical imaging data may include either one of magnetic resonance imaging (MRI) data or computed tomography (CT) data.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • the processes includes creating a tumor volume within the site using the medical imaging data (S 202 ), determining a dose of radiation delivered to the site using the tumor volume(S 203 ), generating a three-dimensional dose grid for the site (S 204 ).
  • the process also includes using the three-dimensional dose grid for the site, calculating a mean dose to a blood pool within the site (S 205 ) and quantifying a total volume of blood receiving radiation (S 206 ).
  • one suitable patient may have at least one tumor at the site of interest in need of radiation therapy.
  • the site of interest may include any suitable tissues or organs in a patient.
  • the site of interest may be head.
  • the tumor volume may be in any suitable shapes.
  • the tumor volume may be spherical.
  • the CT scan or MRI data may be loaded into a first program in a computer system, wherein a spherical tumor volume of the site is created.
  • the spherical tumor volume may be centered in the falx superior to the lateral ventricles.
  • the first program may be a commercially available program.
  • the first program is the PinnacleTM radiation treatment planning system (Version 9.0, Philips Inc., Madison, Wis.).
  • a dose of radiation delivered to the site using the tumor volume may be determined.
  • the dose to the site of interest may be calculated by using a software program, such as the first program.
  • three-dimensional dose grid for the site may be generated.
  • head is the site of the interest
  • the entire site of interest may be delineated and a treatment plan may be then generated resulting in a calculation for the dose, for example, voxelized in 0.4 mm 3 voxels.
  • a mean dose to a blood pool may be calculated and a dose volume histogram may be generated.
  • the three-dimensional dose grid for the site may be analyzed by using a software program, such as a second program.
  • a software program such as a second program.
  • the second program is an in-house software program written in MATLAB (version R2011b, Mathworks, Inc., Natick, Mass.).
  • the present method may use a four-field conformal plan that treats the planning target volume (PTV) to a homogeneous dose.
  • PTV planning target volume
  • a 3D-conformal plan using wedges and five fields may be calculated, and an intensity-modulated radiotherapy (IMRT) plan, for example that using a 2-cm wide sliding window, and an inverse planning approach may also be calculated.
  • IMRT intensity-modulated radiotherapy
  • the dose may be extracted beam-by-beam for the plans other than IMRT and segment-by-segment for IMRT.
  • the present method may use the dose to the brain during a normal course of radiation therapy (RT) as its input.
  • the present method may then use calculate the associated dose to blood circulating through this radiation field.
  • RT radiation therapy
  • the assumptions may include those as follow:
  • One further assumption may be that blood could pass through the beam multiple times but that during the duration of a single beam and/or segment, blood does not reenter the treatment field.
  • the amount of blood transiting through the irradiated zone may be calculated: specifically, as the voxel of blood flows through an irradiated voxel, the dose received is incremented by the dose delivered during the time it takes for the blood to transit through the voxel.
  • Each blood voxel is followed or moved incrementally in the direction of blood flow specific to the anatomical region under treatment until the treatment time ends or the blood voxel exits the site.
  • the dose tally for each blood voxel, i is the sum of doses received in the different physical voxels j through which the blood transited:
  • D i ⁇ j ⁇ dD j dt ⁇ t j , wherein dD j /dt is the dose rate voxel j and t j is the time the blood took to transit through voxel j with beam on.
  • dD j /dt is the dose rate voxel j
  • t j is the time the blood took to transit through voxel j with beam on.
  • the process is repeated, but the total blood voxel dose from each beam or each fraction is convolved with the dose distribution obtained from previous beams or fractions (which supposes a known volume of blood and blood voxels).
  • the cellular component of interest (lymphocytes) in the circulating blood may have reserves in the body that may be released subsequent to initial radiation and may be potentially by replenished; therefore a compartmental model which supplements the blood dose model to calculate dose distribution to the lymphocyte population including cells present in the blood initially as well as radiation treatment progresses which will be different from the generic blood volume dose distribution is desirable.
  • the compartmental model assumes replenishment proportional to the reserve, meaning that it is characterized by a set of first order differential equations:
  • N k ⁇ ( n + 1 ) N k ⁇ ( n ) + 1 6 ⁇ ( k k ⁇ ⁇ 0 + 2 ⁇ k k ⁇ ⁇ 1 + 2 ⁇ k k ⁇ ⁇ 2 + k k ⁇ ⁇ 3 ) where:
  • a total volume of blood receiving radiation may be quantified.
  • one may quantify a total volume of blood receiving any specific dose of radiation.
  • the specific dose of radiation may be 0.5 Gy.
  • the specific dose of radiation of 0.5 Gy may be chosen based on in vitro data on lymphocyte radiosensitivity that showed a D10 (dose required to reduce the surviving lymphocyte population to 10% of initial values) of ⁇ 3 Gy, a D 50 of ⁇ 2 Gy, and a D 90 of ⁇ 0.5 Gy [Nakamura N, Kusunoki Y, Akiyama M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiat Res 1990; 123(2):224-227].
  • the present method may be used to calculate the dose parameters for PTVs of any suitable sizes.
  • the present method may be used to calculate the dose parameters for PTVs of two sizes: 2-cm diameter (4.2 cm 3 volume) and 8-cm diameter (268 cm 3 volume).
  • the present method may be applicable to calculate the dose parameters for plans administered at varying dose rates, for example 300, 600, and 1,200 MU/min, and various radiation techniques, for example IMRT and 3D-conformal.
  • a report of radiation dose received by circulating blood may be generated.
  • one may model the radiation dose delivered to circulating blood during a typical partial intracranial field in an effort to determine the role of radiation in the observed lymphopenia.
  • the result from the present method indicates that a single fraction (2 Gy) delivered 0.5 Gy to 4.6% of the total blood pool. After 10 fractions (20 Gy), 61.5% of the blood pool received 0.5 Gy, and after 20 fractions (40 Gy), 92.2% of the blood pool received 0.5 Gy.
  • a typical 60-Gy radiation treatment plan to the brain (2 Gy ⁇ 30 fractions to an 8-cm diameter field)
  • 98.8% of all circulating blood receives at least 0.5 Gy.
  • Mean dose to the blood pool was 2.2 Gy for a 60-Gy course with a PTV of 268 cm 2 at a dose rate of 600 MU/min. According to the model, as the total dose and the number of fractions increase, the percentage of blood receiving 0.5 Gy increases rapidly.
  • the present method may be used to compare dose to the blood pool for different treatment techniques, such as IMRT and 3D-conformal treatment techniques.
  • IMRT and 3D-conformal treatment techniques were compared, Applicants found that by the end of a 60 Gy plan administered in 30 2-Gy fractions to an 8-cm diameter PTV, no differences were observed in the mean dose to the blood pool or in the proportion of blood receiving 0.5 Gy. Mean dose to the blood pool was 2.4 Gy for the tested 3D-conformal plan and 2.7 Gy for the tested IMRT plan. In both cases, nearly all of the blood received at least 0.5 Gy after 30 2-Gy fractions.
  • Major differences in target volume size may have a significant impact on the mean dose to the blood pool, particularly at higher doses (See FIG. 4 ).
  • the mean blood dose was 2.2 Gy for an 8-cm diameter PTV but was 0.3 Gy for a 2-cm diameter PTV.
  • These data were also analyzed in terms of the percent of blood receiving at least 0.5 Gy, as shown in FIG. 5 . Smaller PTV size MAY decrease CBD.
  • Applicants have identified circulating blood as an organ at risk in radiation therapy by using the present method. Applicants found that standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Applicants' result by using the present invention shows that novel approaches may be needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with high grade gliomas (HGG).
  • HOG high grade gliomas
  • the present invention discloses a computer system for calculating the radiation dose received by circulating blood cells such as lymphocytes.
  • the computer system may use the methods as discussed above to calculate the radiation dose received by circulating blood cells such as lymphocytes.
  • the computer system may include a non-transitory, computer readable storage medium having instructions stored thereon that, when executed by a computer processor, cause the computer processor to undertake the steps of creating a tumor volume within the site using the medical imaging data; determining a dose of radiation delivered to the site using the tumor volume; generating a three-dimensional dose grid for the site; calculating a mean dose of radiation to a blood pool within the site; and quantifying a total volume of blood receiving radiation.
  • FIG. 6 is a block diagram showing an exemplary computer system for calculating the radiation dose received by circulating blood cells such as lymphocytes consistent with the disclosed embodiments.
  • a computer system 600 for calculating the radiation dose received by circulating blood cells may include an input interface unit 601 , a processor 602 , a display device 603 , a random access memory (RAM) unit 604 , a read-only memory (ROM) unit 605 , a communication interface 606 , and a driving unit 607 .
  • RAM random access memory
  • ROM read-only memory
  • Other components may be added and certain devices may be removed without departing from the principles of the disclosed embodiments.
  • a pre-obtained medical imaging data such as CT scan or MRI information of a site in a patient may be entered into the system.
  • the present computer system may be applicable for calculating the radiation dose received by circulating blood cells of any suitable sites in a patient.
  • the suitable site may be head, heart, lung, and others.
  • a suitable site may be head.
  • the input interface unit 601 may include any suitable data input means as understood by a person having ordinary skill in the art.
  • the input interface unit 601 may include any appropriate input device, one or more mass storage devices for storing data.
  • the processor 602 in the computer system may operate under instructions of software programs, such as a first program and a second program to calculate radiation doses received by circulating blood cells.
  • the first program may be a commercially available program such as the PinnacleTM radiation treatment planning system (Version 9.0, Philips Inc., Madison, Wis.).
  • the processor 602 may create a tumor volume with a specific shape, e.g., spherical, calculate dose to the site, delineate the entire site and generate a three-dimensional dose grid for the site.
  • the second program may be an in-house software program, for example that written in MATLAB (version R2011b, Mathworks, Inc., Natick, Mass.).
  • the processor 502 may analyze the three-dimensional dose grid for the site and calculate a mean dose to the total blood pool and quantify the total volume of blood receiving radiation.
  • the processor 502 may also model the radiation dose delivered to circulating blood.
  • the computer processor may further undertake the step of generating a report indicating the quantity of radiation received by circulating blood within the subject.
  • many subject/treatment-specific variables may be considered. Some of the variables may include target volume size associated with the dose of radiation, a radiation treatment technique associated with the dose of radiation, a dose rate associated with the dose of radiation, a total dose associated with the dose of radiation, a fraction size associated with the dose of radiation, a treatment time associated with delivering the dose of radiation, a speed of circulating blood within the subject, and a presence of vasculature relative to the treatment site.
  • the subject/treatment-specific variables may include target volume size and number of radiation fractions as key predictors of dose to circulating blood.
  • the computer processor under instructions of computer readable storage mediums may further undertake the step of generating a report indicating the quantity of radiation received by circulating blood within the subject.
  • the computer processor under instructions of computer readable storage mediums may further undertake the step of determining organs within the subject that are at risk of being subjected to an undesired dose of radiation due to the radiation received by circulating blood within the subject.
  • the computer processor under instructions of computer readable storage mediums may further undertake the steps of creating a tumor volume within the site using the medical imaging data; determining a dose of radiation delivered to the site using the tumor volume; generating a three-dimensional dose grid for the site; using the three-dimensional dose grid for the site, calculating a mean dose of radiation to a blood pool within the site; and quantifying a total volume of blood receiving radiation.
  • the processor 502 may operate under the instruction of non-transitive a computer-readable program or media.
  • a computer-readable program or media for operating a processor is well known to a person having ordinary skill in the art.
  • Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer.
  • the processor 502 may include any appropriate type of graphic processing unit (GPU), general-purpose microprocessor, digital signal processor (DSP) or microcontroller, and application specific integrated circuit (ASIC), and the like.
  • the processor 502 may execute sequences of computer program instructions to perform various processes associated with the calculation of radiation doses received by circulating blood cells as discussed above and following hereafter.
  • a processor will receive instructions and data from a read only memory (ROM) or a random access memory (RAM) or both.
  • the essential elements of a computer are a processor for performing actions in accordance with instructions and one or more memory devices for storing instructions and data.
  • the computer program instructions for the calculation of radiation doses received by circulating blood cells may be loaded into RAM 504 for execution by the processor 502 from the read-only memory (ROM) 505 .
  • Devices suitable for storing computer program instructions and data may also include all forms of non-volatile memory, media, and memory devices, including by way of example semiconductor memory devices, for example, EPROM, EEPROM, and flash memory devices; magnetic disks, for example, internal hard disks or removable disks; magneto optical disks; and CD ROM and DVD-ROM disks.
  • semiconductor memory devices for example, EPROM, EEPROM, and flash memory devices
  • magnetic disks for example, internal hard disks or removable disks
  • magneto optical disks magneto optical disks
  • CD ROM and DVD-ROM disks CD ROM and DVD-ROM disks

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EP3752247B1 (fr) * 2018-02-13 2024-04-10 The Trustees Of Indiana University Calcul de dose immunitaire pour optimisation de plan de traitement en radiothérapie
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US20230264046A1 (en) * 2020-06-18 2023-08-24 H. Lee Moffitt Cancer Center And Research Institute, Inc. Systems and methods for assessing patient-specific evolution of resistance to therapy and progression of disease
WO2023102152A2 (fr) * 2021-12-02 2023-06-08 University Of Virginia Patent Foundation Système, méthode et support lisible par ordinateur pour optimiser une radiothérapie pour un sujet

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US20070088573A1 (en) 2005-10-14 2007-04-19 Ruchala Kenneth J Method and interface for adaptive radiation therapy
US20080292055A1 (en) 2005-11-21 2008-11-27 The Regents Of The University Of California Method for computing patient radiation dose in computed tomography

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US5458125A (en) 1994-01-28 1995-10-17 Board Of Directors Of The Leland Standford Jr. University Treatment planning method and apparatus for radiosurgery and radiation therapy
US20070088573A1 (en) 2005-10-14 2007-04-19 Ruchala Kenneth J Method and interface for adaptive radiation therapy
US20080292055A1 (en) 2005-11-21 2008-11-27 The Regents Of The University Of California Method for computing patient radiation dose in computed tomography

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